The effect of a prolonged in vitro exposure to 1-beta-D arabinofuranosylcytosine and deoxycytidine on the survival of normal (CFU-GM) and leukemic (L-CFU) human myeloid progenitor cells in suspension culture.
We examined the effect of a 96-h exposure to 1-beta-D arabinofuranosylcytosine (Ara-C) and deoxycytidine (dCyd) in medium lacking an exogenous source of colony-stimulating activity (phytohemagglutinin-stimulated leukocyte-conditioned medium, PHA-LCM) on the survival of normal human committed myeloid progenitor cells (day-7 and day-14 granulocyte-macrophage colony-forming units [CFU-GM] as well as leukemic progenitors (leukemic colony-forming units, L-CFU) derived from myeloblasts obtained from 13 patients with acute nonlymphocytic leukemia (ANLL). Coadministration of Ara-C (20-50 microM) in conjunction with dCyd (50-100 microM) permitted the survival of an average of 9%-57% of day-7 CFU-GM and 32%-65% day-14 CFU-GM, depending upon the relative concentrations of dCyd and Ara-C. In contrast, exposure of leukemic myeloblasts to identical regimens resulted in considerably greater reductions in L-CFU survival, which in general exceeded 90% and in some cases was 100%. In addition, exposure of leukemic myeloblasts to Ara-C and dCyd for 96 h in culture medium lacking PHA-LCM eliminated the secondary plating efficiency (PE2) of leukemic colonies in 11 of 13 samples assayed and reduced values dramatically in the remaining 2. Substantial preservation of CFU-GM formation was also noted when normal bone marrow samples depleted of T cells and marrows obtained from two patients with ANLL in remission were assayed. These studies suggest that in contrast to certain normal committed myeloid progenitor cells, leukemic progenitors, particularly those with self-renewal capacity, are highly vulnerable to a prolonged exposure to Ara-C and dCyd in the absence of an exogenous source of colony-stimulating activity. They also raise the possibility that a combined regimen utilizing chemotherapeutic agents in conjunction with modifications of long-term culture techniques may represent a novel approach to the ex vivo purging of leukemic cells from bone marrow in conjunction with autologous bone marrow transplantation.
Grant
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Division of Hematology/Oncology, Medical College of Virginia, Richmond.
Bhalla
K
K
Arlin
Z
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Howe
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CW
D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology*; D003841:Deoxycytidine / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010835:Phytohemagglutinins / Q000494:pharmacology; D013535:Suspensions; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003470:Culture Media; D010835:Phytohemagglutinins; D013535:Suspensions; D003561:Cytarabine; D003841:Deoxycytidine; D003520:Cyclophosphamide; C011272:perfosfamide